The long-term goal of this program is to optimize the application of hyperthermia (HT) as an adjuvant to radiotherapy (RT) and/or chemotherapy (CT). The strengths of this program have been its emphasis on thermal dosimetry and the inter-relationships between HT and tumor physiology. The strengths continue, but in the context of new clinical trials and novel therapeutics. A major cornerstone of this competing renewal is the first clinical trial testing non-invasive thermometry in human patients with extremity soft tissue sarcomas. Our prior observations of tumor oxygenation vs. treatment outcome lead us to continue physiologic studies of soft tissue sarcomas and locally advanced breast cancers. Provocative pre-clinical studies and phase I trial results lead us to test HT with drug-containing liposomes, HT mediated immunogene therapy and to continue studies of intraperitoneal (IP) cisplatin thermochemotherapy of ovarian cancer. Project 1, Human Clinical Studies, will conduct nine clinical trials entered on four specific aims. (1) Non-invasive thermometry. (2) Multi- institutional phase III trials testing HT as an adjuvant to CT and RT in potentially curable patients (advanced high grade soft tissue sarcoma and rectal cancer). (3) Novel therapeutic trials combining HT with doxorubicin-containing liposomes and with IP cisplatin. (4) Continued examination of the role of tumor physiology in HT+RT and HT+CT trials. Project 2. New Hyperthermia Applications in Canine and FELINE Tumors, focuses on novel clinical trials investigating a new low temperature-sensitive liposome formulation and HT triggered immunogene therapy using the HSP70 promoter. Project 3, Delivery of liposomal drugs and gene therapy with heat, will interact with projects 1 and 2 to measure liposomal uptake, drug levels and gene therapy products in patients after HT. The focus of project 4 is on the implementation of the non-invasive thermometry trial. Four cores (Administrative, Animal, Imaging and Engineering) will support the program.